Age-related macular degeneration - the most common cause of severe visual loss in the developed world has a significant genetic component. This fact raises the possibility that the expanding knowledge of the human genome can be used to improve our ability to diagnose and treat this disorder. Recently, we demonstrated that mutations in the gene encoding an extracellular matrix protein known as fibulin 5 are responsible for a statistically significant subset of age-related macular degeneration. In this proposal, we will pursue this discovery at four different levels. First we will screen portions of three fibulin genes (2, 5, and 6) in the cohort of AMD patients and controls that were gathered as part of the Age-Related Eye Disease Study (AREDS) to determine whether our previous results can be confirmed in this well characterized group of individuals. We will also use a novel, focused screening approach to evaluate a minimum of 25 other genes whose proteins are functionally related to the fibulins to determine whether any of these are also involved in the pathogenesis of AMD. In addition, we will explore the pathophysiology of fibulin associated AMD at the tissue level by carefully evaluating the eyes of mice with abnormalities in fibulins 2, 3 and 5 as well as by crossing these mice to ABCA4 deficient mice in an attempt to augment their phenotype. Finally, we will carefully study 37 human kindreds already known to harbor mutations in fibulin genes to test the hypothesis that the phenotype we observed in the fibulin 5 patients in our previous study is characteristic of fibulin associated AMD as a whole. This part of the study will also assess the age-dependent penetrance of fibulin mutations in these kindreds, which will be a critical factor in determining whether large scale molecular testing for fibulin variations will someday be of value.